Enhanced learning ability by use of thioridazine

ABSTRACT

Thioridazine is useful in enhancing the learning process of mammals.

United States Patent Gogerty Apr. 22, 1975 ENHANCED LEARNING ABILITY BYUSE 1961, pp. 823-827.

OF TIIIORIDAZINE [75] Inventor: John H. Gogerty, Dover. NJ.

Primary Eraminer-Stanley J. Friedman [73] Asslgnee: sandoz'wander'Hunm'eL Attorney, Agent, or FirmGerald D. Sharkin; Robert 22 Filed:Sept. 28, 1973 Honor 21 Appl. N0.: 401,947

[52] [1.8. CI. 424/247 5 ABSTRACT [51] Int. Cl A6lk 27/00 [58] Field ofSearch 424/247 Thioridazine IS useful in enhancing the learning pro-[56] References Cited 9988 of mammals- OTHER PU BLICATIONS Aceto et al.Journal of Pharm. Sciences. Vol. 50,

3 Claims, No Drawings ENHANCED LEARNING ABILITY BY USE OF TI-IIORIDAZINEThis invention concerns the use of thioridazine in enhancing the processand degree of learning which thereby assists in improving intelligenceand knowledge of mammals.

It has been observed in the recent past that Thioridazine is useful inavoiding interference with normal paradoxical (REM) sleep. Intake ofhabit forming or other drugs or alcohol cause such interference.Moreover, correlations established between learning and brain proteinsynthesis on one hand and amount of REM sleep time and protein synthesison the other hand indicated to the instant inventor that certainexperiments be performed which show a correlation between administrationof Thioridazine and degree or rate of learning of mammals. Certainexperimental procedures described more fully hereinafter were performedto test this correlation.

The instant invention accordingly provides a method for increasing thelearning rate and ability of mammals by administration of Thioridazinein a manner so as to permit increased REM sleep in said mammals.

Because of variation of the normal or usual sleep time patterns ofvarious species of mammals and individuals within one species, it willbe understood that the appropriate time as well as the appropriatequantity for administration of Thioridazine will vary. Normally,Thioridazine may be combined with one or more pharmaceuticallyacceptable carriers or adjuvants and administered orally orparenterally. The desired dosage will vary depending upon the mode ofadministration and the reaction to treatment of the individual mammalsinvolved. In general, however, it is desired that for purposes of thisinvention, mammals be administered Thioridazine at a daily dosage ofabout 0.18-30 mg/kg of animal body weight, and at a single dosage ofabout 0.18-15 mg/kg of animal body weight. It is preferred that at leastone administration of Thioridazine take place within about one hour ofthe mammals major normal sleep period or periods. For most largeanimals, the total dosage is from about -200 mg. per day, preferably inintimate admixture with a solid or liquid pharmaceutically acceptablecarrier.

The effect of Thioridazine on REM sleep has been noted by virtue oftests performed in cats and cebus monkeys orally administered about0.18- mg/kg of animal body weight of Thioridazine by use of chronicallyimplanted electrodes.

Monopolar cortical leads on the sensory motor and occipital cortices andan electro-oculogram were recorded via stainless steel screws. Bipolarconcentric subcortical leads include the amygdala, hippocampus, septum,medium forebrain bundle, hypothalmus, olfactory bulb, anterior andposterior reticular formation and the lateral geniculate nucleus-of thethalamus were among the sites used for implantations. The exposed tipbarrel. Brain readings were obtained via Grass Model 6, 10 or 16 channelelectroencephalographs.

For the recording sessions, the test animals were placed in LehighValley Electronics full side observation cages at the same time everyday for either 4 or 8 hours (cats) or every night for 13 /2 hours(monkeys). After 4 hours (during the 8 hour studies) the cats wereallowed free access to food and water for 30 minutes. The monkeys wereplaced in their home cages and given free access to food and waterduring the day.

Outside noise was masked by background white noise. Gross behavior wasmonitored via closed circuit television and video tape recordings.

Control data were collected at least 2 days per week i and accumulatedto give control data for 10 to 20 sessions per cat or monkey.

Thioridazine was administered either stat, 15 or 30 minutes prior toplacing the animals in the observation cages. Physiological saline wasadministered via similar routes and preinjection times (as above) on allcontrol runs. Data from each session were statistically compared (viacomputer analysis) to the previous 10-20 control sessions for thatparticular animal, with particular emphasis given to the followingphases of the sleepwakefulness cycle: resting awake, light sleep, deepsleep, paradoxical (REM) sleep, pseudoparadoxical sleep, latency toonset of first epoch of paradoxical sleep.

The method by which increased REM sleep was noted in the test animalswas by observing the decrease in muscle tone while the animal isbehaviorly asleep and eye movement increases. It is noted that thiseffect always follows'a transitional activity characterized by neuronalspiking in the lateral geniculate nucleus and- /or the occipital cortexof the test animal.

In order to ascertain whether administration of Thioridazine inaccordance with this invention was consistent with experimentalevidence, six naive cebus monkeys were trained to lever press to obtainbananaflavored pellets and were started on a simple CRF (continuousreinforcement) schedule. Each bar press resulted in reward of onepellet. Criteria for rate of learning was speed at which total reward ofpellets per session was achieved.

On the basis of the results of the CRF test, the six monkeys were rankedwith respect to smartness, i.e., No. 1 monkey was the fastest learner,No. 2 next, etc. In this context, it was assumed that smartness wasrelated to motivation to obtain food. The animals were then trained on aschedule whereby after a total of one pellet was rewarded 10 barpresses.

The monkeys were then divided into 2 groups: Nos. 1, 3 and 5 monkey wereadministered oral saline and Nos. 2, 4 and 6 monkey were givenThioridazine at 7.5 mg/kg p.o. for 22 days. Dosing was from 4-5 PM dailyand the animals were allowed to sleep in their own cage to learn aschedule whereby a pellet is rewarded only when a bar press was precededby a 30-second period without a bar press (DRL schedule). The resultswere of the electrode extended 05-075 mm. beyond the 60 as follows:

Mon- Day No.

key No. Results 1 3 5 7 9 ll l3 l5 17 19 21 24 Absolute Reinforcement 3731 36 25 34 78 93 121 99 H8 1 Change from ay 6 1 l2 3 M 56 84 68 62 8173 Absolute Reinforcement 2 6 38 42 26 57 55 65 57 5O 46 49 -ContinuedMon- Day No.

key No. Results 1 3 5 7 9 ll l3 l5 l7 l9 2] 24 Change from pu l 4 36 402.4 55 53 e3 55 4s 44 47 50 UK? Reinforcement 8 Z 7 l0 2 ll l0 l2 I7 5335 50 Change from Day 1 -6 -l 2 6 3 2 4 9 45 27 42 AbsoluteReinforcement 6 20 17 24 42 35 42 38 4] 67 4 Change from pu l 14 l1 l8 936 29 14 36 32 35 61 SO UH) Reinforcement 3 2 l 4 l 3 3 l 2 2 2 9 5Change from Day I l 2 1 2 0 0 2 -1 -l 1 6 Ahsolute Reinforcement 4 3 4 7l3 54 7] 55 63 6l 70 88 Change from Day I l 0 3 9 5O 67 SI 59 57 66 84The results show the relationship between change in istration aretablets or capsules prepared by standard the number of reinforcements(the pellets received techniques which contain the following: over andabove that received on the first day) and days on experiment. Note thatthe No. l monkey, which was weight (m g the fastest learner in this CRFtest, learned the DRL Tablet Capsule test at the same time that theslowest Mellaril-dosed monkey did. This experiment indicates thatThioridag q i g ig USP g8 g8 zine is able to enhance learning. jfifg f ig As used herein, the term normal sleep is intended fire-dried fumedsilica) 2 to represent the longer and/or longest periods of sleep(refined xamhan gum) 25 I obtained on a normal daily basis by a mammal,whether Lactose, USP 4 138 y n or y an: new" 83 lt Wlll be understoodthat enhanced learning com- TOTAL 260 260 prises both increased capacityfor learning as well as increased rate of learning and both concepts areinfwdcmark. 2 E P PT'wtended to be included in the present invention.Trademark Thioridazine may be similarly administered in the w is claimedform of its nontoxic pharmaceutically acceptable acid L A method f renhancing learning comprising adf f Salts Such salts posses the sameorder of ministering to a mammal in which learning is desired to tmty asfree base y prepared by reacnng be enhanced 10200 mg. of Thioridazine ora pharmathe base with an appropriate acid and accordingly are ceuticanyacceptable salt th f included within the scope of the invention.Representa- A method according to claim 1 wherein the i 3; ?r223:32:2zsgiggf xggg lfigi e 1:623:12 ?:2; istration takes place within aboutone hour before the mammals normal sleep time. the like and the organicacid salts, such as the succrn- 3' A method according to claim 1 whereinthe Thioig ll li fuma'ate acetate p'toluenesulfonate and ridazine isadministered before the normal sleep time of the mammal. Representativeformulations suitable for oral admm-

1. A METHOD FOR ENHANCING LEARNING COMPRISING ADMINISTERING TO A MAMMALIN WHICH LEARNING IS DESIRED TO BE ENHANCED 10-200 MG. OF THIOIDAZINE ORA PHARMACEUTICALLY ACCEPTABLE SALT THEREOF.
 1. A method for enhancinglearning comprising administering to a mammal in which learning isdesired to be enhanced 10-200 mg. of Thioridazine or a pharmaceuticallyacceptable salt thereof.
 2. A method according to claim 1 wherein theadministration takes place within about one hour before the mammal''snormal sleep time.